Nutrition no cure for schizophrenia
BYLINE: DAVID IRWIN; VANCOUVER SUN
I was disappointed to read Dr. Carolyn DeMarco's column promoting high
dose vitamin treatments for schizophrenia. At a time of real progress
in treatment of schizophrenia, Dr. DeMarco has written about an approach
which Dr. Abram Hoffer and others developed in the 1950s, but which
by the 1970s was proven to be fruitless. The work of Dr. Hoffer and
others is discussed in detail in the American Psychiatric Association
Task Force Report, July 1973, which points out methodological flaws
in the early work and reviews later studies which failed to show any
benefit for such treatments.
In recent years, new medicines, with improved side-effect profiles
and techniques to overcome problems with social and occupational functioning,
have been well proven advances for the treatment of schizophrenia. Early
intervention programs should prevent some of the serious dysfunction
of the disease.
Serious illnesses like schizophrenia require proven treatments. Vitamin
treatments as "alternative" therapy for schizophrenia should
not be recommended.
David Irwin, MD
Department of Psychiatry
Vancouver General Hospital
Source: The Vancouver Sun, January 23, 1998
Eye Movement Studies To Help Diagnose Mental Illness
Researchers at the University of Illinois at Chicago are studying subtle
abnormalities in eye movements that may one day be used to diagnose
psychiatric disease. Irregularities in how the eyes track a moving object
reflect defects in the neural circuitry of the brain and appear to correspond
with particular types of mental disorders. Schizophrenic patients, for
example, have difficulty keeping their eyes focused on slow-moving objects.
With new technology, these abnormalities can be measured precisely
and compared with normal patterns. "Psychiatric illnesses are not well
understood neurologically," said John Sweeney, director of the Center
for Cognitive Medicine in UIC's department of psychiatry. "Eye movement
tests offer a way to investigate abnormalities in the brain that are
causing these disturbances."
The goal, Sweeney said, is to develop eye movement tests as a simple,
noninvasive tool for diagnosing brain disorders, including schizophrenia,
depression and developmental illnesses such as autism. "At present,
however, the field is still in its infancy," he said.
Under a $1.2 million grant from the National Institute of Mental Health,
Sweeney and his colleagues are testing eye movement patterns in patients
diagnosed with psychotic disorders, including schizophrenia, bipolar
disorder and depression, in order to begin to validate eye movement
abnormalities as markers for different brain diseases.
For these studies, participants undergo a 90-minute series of visual
tests in a specially designed laboratory. Seated in a dark room with
their heads secured in a chin rest, subjects are shown a pinpoint of
light on the opposite wall.
They are asked to focus on the light as it jumps from one spot to another,
to anticipate the location of the light after it has disappeared and
to follow the light as it glides to the left or right at different speeds.
Various tasks are designed to test the function in different parts of
the brain controlling cognitive operations and eye movements.
One task, for example, tests short-term memory. Subjects are shown
a brief flash of light; after a several-second delay, they are asked
to move their eyes to the remembered location. Participants wear infrared
spectacles, called scleral-reflection glasses, which are linked to a
nearby computer that records small movements of the eyes very precisely.
The measurements are made using software developed in Sweeney's laboratory.
Participants also complete similar tasks in an MRI scanner, enabling
the researchers to observe the corresponding brain activity directly.
With the scanner, the brain regions controlling different types of eye
movements are systematically investigated one at a time.
Sweeney and his colleagues, who have been studying eye movement patterns
for 20 years, are using their laboratory to document impairments associated
with disease and injury and to chart the course of brain and cognitive
development from ages 8 to 15.
During that period, the brain undergoes important changes affecting
eye movement control. Neurodevelopmental disorders can interfere with
this maturation. "Eye movement studies provide a noninvasive way to
gain a deeper understanding of the brain dysfunctions at the root of
psychiatric illnesses," said Sweeney.
"We are following patients over time to monitor the progression of
their disease and determine whether different treatments are improving
their brain and cognitive function." With this information Sweeney hopes
to develop the tools needed to improve the diagnosis and treatment of
psychiatric illnesses. "And in the long-term future," he said, "through
our efforts to link eye movement and cognitive abnormalities to their
underlying genetic causes, we hope to be able to identify high-risk
individuals and someday prevent the onset of some of the most common
and severe brain disorders that now overwhelm our mental health treatment
For more information about the UIC department of psychiatry, visit
Editor's Note: The original news release can be found here.
Innovative, Multicenter Study Of Schizophrenia
Will Follow Disease Traits In Hunt For Genetic Causes
Specific information processing abnormalities and brain-related circuit
dysfunction in schizophrenia patients may be the keys to finding the
genetic basis of this puzzling, devastating mental illness that affects
more than two million Americans and one percent of the world's population.
Scientists believe multiple genes cause schizophrenia, but specifically,
the genetic basis of this disorder remains somewhat of a mystery. Research
has pointed to several chromosomes that harbor likely disease-causing
genes, but the search has been unsuccessful for the exact genetic code
that causes this devastating, but elusive disorder.
Now, with a $20-million, five-year grant from the National Institute
of Mental Health, seven academic research centers in the U.S., led by
the University of California, San Diego (UCSD) School of Medicine, are
taking a different approach to uncover the genetic causes of schizophrenia.
Rather than starting with the broadly defined disorder itself, scientists
are beginning with specific physiological markers, or traits, that are
characteristic of schizophrenia in both patients and some clinically
unaffected, normal family members. These physiological markers - caused
by defects in brain circuits - will then be used to identify the complex
genetic abnormalities that cause them.
"I believe our research is an important step in furthering our
understanding of schizophrenia and then identifying the critical, genetically
mediated brain dysfunctions that contribute to the disease," said
David Braff, M.D., UCSD professor of psychiatry and director of the
seven-center Consortium on the Genetics of Schizophrenia (COGS). "Instead
of exploring the genetics of schizophrenia, we're identifying the genetics
of different neurological deficits that occur in schizophrenia patients.
He added that the main research hypothesis is based on the tenants
of molecular biology. "If there are several different genetic abnormalities
associated with schizophrenia, then each of them would cause a change
in a specific protein. We believe that the series of protein changes
in this disease is reflected by corresponding discrete functional abnormalities,
such as disorganized thought processes," Braff said.
This strategy has been used for gene discovery in other complex medical
illnesses. For example, in a form of colon cancer, researchers were
able to identify a gene that causes multiple polyp formation, which
leads to the cancer, rather than finding a gene for the cancer, itself.
At least six specific schizophrenia traits, called endophenotypes,
will be studied in more than 2,000 individuals. UCSD, which is leading
the project, will be joined by researchers at Harvard, Mt. Sinai School
of Medicine, UCLA, University of Colorado Health Sciences Center, University
of Pennsylvania and University of Washington, Seattle. Key to the studies
will be the testing of individuals with schizophrenia and their clinically
unaffected family members. These family members may have the same liability
genes and associated traits, but are normal and don't show clinical
signs of the disease. Specifically, the researchers will study cognitive
dysfunction and abnormalities in perception and information processing
experienced by schizophrenia patients. (See below for descriptions of
For example, schizophrenia patients, family members and "normal"
individuals will be tested for deficits in the ability to inhibit, or
"gate" irrelevant stimuli. People are constantly bombarded
with a multitude of external and internal stimuli, and most individuals
are able to select those stimuli that are most relevant to current activities
and goals, while screening out - or gating - irrelevant stimuli. Schizophrenia
patients are unable to filter the trivial from essential information
and stimuli in everyday sensory input. They, therefore, have troubles
navigating in everyday life activities because they are easily distracted,
confused, and they become disorganized.
The disordered thinking that is characteristic of schizophrenia may
be manifested in some of the more visible features of the disease, such
as disorganization of speech and behavior with associated disabilities
in work and social relationships.
"Ultimately, the COGS study will lead to a better understanding
of the genetic abnormalities associated with these cognitive and information
processing dysfunctions in schizophrenia patients," Braff said.
"On a longer term basis, this functional genetics approach may
lead to a new era of genetically informed treatment options. Thus, medications
will be aimed at reversing genetically mediated brain dysfunctions and
restoring schizophrenia patients to better levels of social and work
function as their symptoms are alleviated."
New dynamic imaging techniques provide a deeper
look at Alzheimer's and schizophrenia (excerpt)
By Robert Adler, Globe Correspondent, 5/6/2003
Paul Thompson, the UCLA neuroscientist whose team created these
first-ever sequences of a disease engulfing the living human brain,
sees [new images they've captured on the disease process of schizophrenia
and alzheimers] as a significant step toward earlier diagnosis,
more effective treatment, and -- eventually -- prevention or cure
of brain-destroying diseases.
Thompson, a 31-year-old British emigrant, is unabashedly excited
about his team's accomplishments: ''The tools from our group are
opening really new windows on what's happening inside the brain.''
They give researchers a powerful way to test new medications and
lets doctors diagnose Alzheimer's and other dementias earlier and
more accurately. That should give more patients an early start on
medications that can at least slow the ravages of these diseases.
Like faces, no two brains are alike. As a result, it's extremely
difficult to compare diseased and healthy brains or track changes
over time. That's the problem Thompson and his team solved. By morphing
ordinary MRI scans onto a standardized brain, they can pool scans
from multiple patients without blurring the picture. They can then
sequence those standardized images into revealing movies. And, crucially,
they can quantify changes with great precision. ''We can code normal
human variation,'' he said, ''and still be exquisitely sensitive
to abnormal changes.''
As a result, Thompson's group has been able to study diseases such
as Alzheimer's and schizophrenia as never before. ''With this kind
of imaging, you can see a lava flow of destruction as more and more
brain tissue is engulfed,'' Thompson said. ''You can see exactly
which areas are losing tissue, when, and how fast.''
Thompson first applied these new tools to schizophrenia....In 2001,
Thompson's group produced the first time-lapse images revealing
a wave of tissue loss rolling across the brains of schizophrenic
children. They utilized high-resolution MRIs of more than 1,000
children scanned every two years since 1992 by Judith Rapoport and
colleagues at the National Institute of Mental Health. Thompson's
group detected the first flicker of the disease in a small part
of the parietal cortex, above and behind the ears.
Over five years, Thompson saw a ''pervasive, unrelenting wave of
tissue loss that swept forward like a forest fire,'' eventually
engulfing the sides and front of the brain. By 18, the teenagers
had lost 25 percent of their gray matter in certain brain areas.
''Seeing that wave of tissue loss in schizophrenia was a huge surprise,''
Thompson said. The pattern matched the drumbeat of schizophrenia's
active and passive symptoms -- hallucinations, delusions and bizarre
thinking followed by flattened emotions, depression and withdrawal.
The images are disturbing but valuable. They've pushed Thompson
toward the theory that schizophrenia is a disrupted version of normal
Teenagers' brains normally undergo extensive ''pruning'' in which
1 percent of the gray matter disappears every year, more in some
areas. Because schizophrenia typically strikes during this process,
Thompson sees it as ''an exaggeration or derailment'' of normal
pruning -- like a gardener gone wild.
His finding that schizophrenia takes up to seven years to engulf
the brain highlights the need for early diagnosis and treatment.
It also makes finding drugs that may salvage young people's brains
even more vital. ''There is a window of opportunity to step in and
oppose the disease,'' he said.
Dynamic brain imaging should also speed up the search for genes
that predispose people to specific brain diseases. We know they're
there. Siblings and children of schizophrenics have one chance in
10 of developing the disease -- 10 times the average risk. A half-dozen
genes already have been linked to Alzheimer's, with more to come.
It is much easier to match suspect genes to specific patterns of
tissue loss than to shifting, hard-to-measure symptoms.
Thompson's movies can be viewed at http://www.loni.ucla.edu/
Changes in glucose and cholesterol levels
in patients with schizophrenia treated with typical or atypical
(American Journal of Psychiatry)
Glucose and cholesterol levels increase when schizophrenia patients
are treated with most of today's anti-psychotic drugs. Clozapine,
olanzapine and haloperidol are associated with increased plasma
glucose level, and clozapine and olanzapine with raised cholesterol,
report researchers in Orangeburg, New York.
Although mean changes in glucose and cholesterol levels remained
within clinically normal ranges, about one patient in seven studied
by the researchers developed abnormally high glucose.
The researchers conducted a 14-week randomised, double-blind trial
which assessed the effects of clozapine, olanzapine, risperidone
and haloperidol on levels of glucose and cholesterol. The study
participants were 101 hospital in-patients with schizophrenia or
American Journal of Psychiatry 2003;160:2:290-296. "Changes
in glucose and cholesterol levels in patients with schizophrenia
treated with typical or atypical antipsychotics."
Gene May Play a Role in Schizophrenia
Excerpt from story by NICHOLAS WADE, New York Times
The long search for a gene that helps cause schizophrenia may
at last be bearing fruit after many false starts and disappointments,
scientists are reporting.
An errant gene first implicated among schizophrenic patients in
Iceland has now turned up in a survey of Scottish patients, too,
giving a clear confirmation of the earlier result.
The gene may be involved in remodeling the connections that brain
cells make with one another, called synapses. Many of the Icelandic
and Scottish patients have the same variant pattern in the gene,
supporting the idea that when the gene does not work as designed,
wrongly formed nerve-to-nerve wiring accumulates in the brain, giving
rise to schizophrenia.
Not all schizophrenics carry the variant and many people carry
it without a problem, an expected pattern in diseases caused by
several genes. But in both populations, inheriting the variant form
of the gene appears to double the risk of schizophrenia.
The finding, if correct, would bolster the strategy followed by
Decode Genetics, a company based in Reykjavik that is using the
Icelandic population to search for the genetic roots of common diseases
like cancer, diabetes, heart disease and Parkinson's. The schizophrenia-related
gene is one of the first it has found.
Dr. Kari Stefansson, a former Harvard neuropathologist who is the
company's chief executive, said Decode and its partner, the drug
company Roche, were developing new drugs to counteract the aberrant
gene's effects but could not say when any would be ready for clinical
A defect in neuregulin-1, he suggested, might lead to an accumulation
of wrongly formed synapses, accounting for the progressive nature
of the disease. It might also explain why environmental factors
as well as heredity contribute to schizophrenia, as shown by the
fact that if one identical twin has the disease the other has only
a 30 to 50 percent chance of developing it.
Dr. Stefansson said he had a considerable emotional investment
in the disease because his elder brother has schizophrenia.
The variation discovered by Decode Genetics is a set of seven genetic
differences that spans the beginning of the neuregulin gene, which
is located on the eighth of the 23 pairs of human chromosomes. Dr.
Stefansson said he guessed that the seven changes might in some
unexplained way be altering the amount of protein the gene could
Dr. Kendler said the progress with the two genes "induces
a bit more optimism in a field that has had some difficult times."
Research may lead to better schizophrenia drugs
July, 6 2003 20:29 , Source: MIT Press Release
The study, reported this week in the early online edition of the
Proceedings of the National Academy of Sciences, may lead to the
first genetically targeted drugs for the disease, which affects
1 percent of the population worldwide.
Nobel laureate Susumu Tonegawa, director of the Picower Center
for Learning and Memory at MIT and a Howard Hughes Medical Institute
investigator, found that genetically engineered mice lacking the
brain protein calcineurin exhibit a number of behavioral abnormalities
shared by schizophrenic patients.
In a related study with researchers at Rockefeller University in
New York, MIT scientists show that variation in a human calcineurin
gene also is associated with schizophrenia. Calcineurin--part of
a biochemical pathway in the brain linked to receptors for two brain
chemicals, NMDA and dopamine--plays a significant role in the central
This is the first study that uses animals who demonstrate an array
of symptoms observed in schizophrenic patients to identify specific
genes that predispose people to the disease.
MICE AND MEMORY
Tonegawa creates tools to explore the genetic underpinnings of
the molecular mechanism for memory. Genetically engineered mice
who are missing the brain enzyme calcineurin were previously shown
to have an impairment in short-term, day-to-day memory formation,
known as working memory. This kind of memory also is impaired in
Further testing of these mice by Picower Center research scientist
Tsuyoshi Miyakawa revealed that they also have attention deficits,
aberrant social behavior and several other abnormalities characteristic
Picower Center research scientist David Gerber then collaborated
with Rockefeller's Maria Karayiorgou to examine calcineurin genes
in DNA samples from schizophrenic patients and their immediate relatives.
The researchers found an association between a particular calcineurin
gene and schizophrenia.
"This is an intriguing series of findings," Tonegawa
said. "The combination of evidence from the genetically altered
mice, together with the human gene studies, create a strong argument
to link calcineurin with schizophrenia."
A SEARCH FOR DRUGS
Alterations in multiple genes are believed to predispose people
to schizophrenia. Tonegawa suspects that many of these genes may
turn out to be components of the calcineurin pathway or to directly
interact with the calcineurin pathway.
"Once we better understand exactly which genes are involved,
we will know how proteins are affected, and we can set up a test
to screen large numbers of compounds to identify ones that have
desired effects on the activity of these proteins," Tonegawa
said. "This can potentially lead to the discovery of new kinds
of drugs for psychiatric conditions such as schizophrenia."
In addition to Gerber, Miyakawa, Karayiorgou and Tonegawa, co-authors
include Joseph A. Gogos of Columbia University, and Diana Hall and
Sandra Demars of Rockefeller University. Authors on the mouse study
include research specialist Lorene M. Leiter and Hongkui Zeng of
MIT, and Raul R. Gainetdinov, Tatyana D. Sotnikova and Marc G. Caron
of Duke University.
The study on the human genes associated with schizophrenia susceptibility
was funded by the Picower Foundation, the National Institutes of
Health, the Howard Hughes Medical Institute, the Otsuka Maryland
Research Institute, the McKnight Endowment Fund for Neuroscience,
the EJLB Foundation and the New York City Council Speaker's Fund.
The study on the genetically altered schizophrenic mice was funded
by the Picower Foundation, the National Institutes of Health, the
Howard Hughes Medical Institute, RIKEN and NARSAD.
Leading Drugs for Psychosis Come Under New Scrutiny
Excerpt from Story by ERICA GOODE, New York Times
They were billed as near wonder drugs, much safer and more effective
in treating schizophrenia than anything that had come before.
For many years, it seemed that the excitement was fully warranted.
There were remarkable stories of recovery. And the new generation of
antipsychotic drugs, called atypicals, seemed to have few of the side
effects commonly seen with high doses of older medications for psychosis.
The drugs appeared so successful that doctors began prescribing them
for other things, not only for other psychotic illnesses, like manic
depression, but also for Alzheimer's, personality disorders and nonpsychotic
depression, and for conduct disorder and severe aggression in children.
Sales of the drugs soared. More than 15 million prescriptions were written
last year for the two leading drugs alone, Zyprexa and Risperdal, industry
But 14 years after the first of the drugs entered the market, researchers
are questioning whether they are quite as miraculous - or benign - as
The first round of antipsychotics had such unpleasant side effects,
like dry mouth, stiffness and trembling, that people often just stopped
using them. The atypicals are considered by many patients to be more
tolerable, and many experts believe they are better than older drugs
in treating some aspects of psychosis.
But studies suggest that their superiority is at best modest, specific
to certain symptoms and variable from drug to drug. Also, there is increasing
suspicion that they may cause serious side effects, notably diabetes,
in some cases leading to death.
The issue of risks has become more pressing as the drugs are prescribed
for children and for adults with milder conditions. And the states,
which pay enormous sums for the atypicals in caring for the severely
mentally ill, are questioning whether the benefits of the new drugs
are worth their costs.
The drugs, experts say, have now reached a turning point where benefits
must be balanced by side effects and cost.
National sales of antipsychotics reached $6.4 billion in 2002, making
them the fourth-highest-selling class of drugs, behind cholesterol-lowering
drugs, ulcer drugs and antidepressants, said IMS Health, a company that
tracks drug sales. According to NDCHealth, another company that tracks
the industry, in 2002, more than 7.4 million prescriptions were written
for Zyprexa and more than 7.6 million for Risperdal.
Many doctors and patients prefer the drugs to the older medications.
Bretta M., 34, a Brooklyn woman, for example, said that the Zyprexa
she takes is an improvement over Haldol, an old-generation drug that
she said made her feel "like a zombie."
"I'm less stiff," Bretta M. said. "I can concentrate
more. I'm more alert."
But the drugs have hardly proved to be a panacea, experts say, and
some are more effective and less likely to cause the side effects of
older medications than others.
"There has been what I see as a kind of myth-making," said
Dr. William Carpenter, a professor of psychiatry and pharmacology at
the University of Maryland and the director of the Maryland Psychiatric
Research Center. "It's like: `The new generation of drugs is safe,
patients like them and they're more effective.' "
"Patients probably do like them a little bit more," Dr. Carpenter
said, and therefore might be slightly more likely to keep taking their
medication. "But we still have plenty of trouble with the new-generation
Like other experts, Dr. Carpenter believes that the atypicals have
an edge over the older drugs in some areas. He and others said they
seem better at easing the emotional blunting, withdrawal and depression
often seen in schizophrenia.
Studies have indicated that they are better at preventing relapse and
that they carry a lower risk of the most pernicious side effect of older
drugs: tardive dyskinesia, a disorder that causes repetitive movements
- chewing motions, lip-smacking and contortions of the arms and legs
- that sometimes persisted even after the drugs were stopped.
The drugs may help with problems in memory, decision-making and other
mental functions that can keep schizophrenia patients from working,
but this is still debated.
"I think the new-generation drugs have shown advantages,"
said Dr. John Kane, the chairman of psychiatry at Zucker Hillside Hospital
in Queens and an expert on schizophrenia. "They may not be consistent
across every study or every drug, but when you take them in their totality,
they are meaningful."
But determining how much more effective the drugs are is not easy.
As in all areas of medicine, many studies, including those that appear
in peer-reviewed journals, are financed by drug companies. Others are
financed by government insurers.
Complicating matters further, many studies are small and they use a
variety of methodologies, making comparison difficult.
Analyses that examine the findings from many studies have come up with
mixed results. For example, in a presentation at a schizophrenia meeting
last month, Dr. John Davis, a professor of psychiatry at the University
of Illinois at Chicago, reported on an analysis of 124 studies comparing
newer and older drugs. Ten atypical antipsychotics were included, some
of them available only in Europe. Five of the newer drugs, including
two not on the market here, were moderately more effective in treating
psychotic symptoms than the conventional treatments, the analysis found.
Of those sold here, Clozaril was the most effective, followed by Risperdal
and Zyprexa. Four of the drugs, however, offered no advantage, and one
drug, sold only in Europe, was actually worse. Dr. Davis said he received
no financing from pharmaceutical companies for his research.
But a 2000 analysis, by Dr. John Geddes, a psychiatrist at the University
of Oxford, created a stir by finding no difference in effectiveness
between the two classes of drugs. The study, financed by the British
government and published in the British Medical Journal, examined 52
studies comparing atypicals and older drugs.
Some patient-advocacy groups have criticized the study as biased toward
the lower-cost, older-generation drugs.
In a telephone interview, Dr. Geddes said that, like other clinicians,
he had seen patients improve remarkably on the newer medications. "But
I remember over the last 20 years I had quite a lot of people who did
really well on the older ones, too," he said.
Part of what gave the older drugs a bad reputation, Dr. Geddes contends,
was that in the past they were given in very high doses that may have
made them less effective and increased side effects. Too, he said, many
atypicals "were quite new, and it's not good to go spraying around
new drugs without knowing about the long-term effects."
In a report this month in The Lancet, the medical journal, Dr. Stefan
Leucht, a research associate at Zucker Hillside Hospital, and his colleagues
found that although most atypicals produced fewer Parkinson's-like side
effects than high-potency older drugs like Haldol, when compared with
older drugs of lower potency, some of the new drugs were just as likely
to cause the side effects.
The analysis indicated that only Clozaril and, by a hair, Zyprexa had
fewer of the side effects than the conventional antipsychotics, while
the other drugs, including Risperdal, showed no fewer side effects.
Dr. Leucht cautioned that the number of studies examined in the analysis
was small and that the findings needed confirmation through further
Joel Yates of Brooklyn, 53, who has schizo-affective disorder, said
he took Haldol at low doses for 15 years and had no bad side effects.
Three months ago, Mr. Yates's doctor, concerned about the risk of tardive
dyskinesia, switched him to Abilify, a new atypical.
"It's hard to notice any particular difference," Mr. Yates
But Regina Moran, a spokeswoman for Novartis, the maker of Clozaril,
said that the atypicals had made a large difference for many patients
and their families. Before the drugs, she said, "there were many,
many schizophrenic patients who never left the back wards of mental
Researchers say the final verdict is not in.
Some experts hope that a large study comparing atypical and traditional
antipsychotics, underwritten by the National Institute of Mental Health
and directed by Dr. Lieberman, will help resolve the issue when its
results come out next year.
Even less is known about how the drugs affect children. Psychiatrists
say they are helpful and necessary for children who suffer from psychosis
or who demonstrate severe aggression. But there is so far little data
on their effectiveness or safety, though pharmaceutical companies are
now beginning to study the drugs in children and adolescents.
The Side Effects`Thorazine Shuffle' Vs. Diabetes
Old antipsychotic drugs were notorious for their side effects, not
only tardive dyskinesia but the dull-eyed stare and stiff-legged walk
that became known in the back wards of state hospitals as the Thorazine
Such problems are less frequent in the newer generation of drugs, but
they are not unheard of. If researchers agree on anything, it is that
the new medications have side effects of their own, some serious.
Most disturbing are cases of diabetes, Type II and Type I, and hyperglycemia
that have been reported in adults and some children taking atypical
antipsychotics. A study presented yesterday at the psychiatric meetings
by Dr. P. Murali Doraiswamy, chief of the division of biological psychiatry
at Duke University, and his colleagues raises the possibility that some
newer drugs may also be linked to pancreatitis.
Excessive weight gain is common on some atypicals, and may be linked
to cases of diabetes: Some patients have reported gaining up to 65 pounds.
Some developed diabetes or glucose abnormalities after gaining weight.
Others already had the disease and grew worse while taking the drugs.
Still others fell ill quickly after starting an atypical and got better
once the drug was stopped. For some, the illness was fatal.
Many experts suspect that the drugs are somehow causing or bringing
out diabetes and that some drugs may do so more than others. But they
are not yet certain that this is the case. Nor do they know how big
the problem is. The number of reported cases so far is relatively small,
given the many millions of people who have taken the drugs. More than
12 million people have taken Zyprexa alone, according to Eli Lilly.
Complicating matters further, diabetes is common and increasing in
the general population. And some studies of patients in the 1940's suggest
that diabetes may be higher in people with schizophrenia even without
But the cases are worrisome because it took many years for psychiatrists
to recognize that the older drugs were causing tardive dyskinesia.
In three studies, researchers led by Dr. Elizabeth A. Koller examined
cases of diabetes in patients taking Clozaril, Zyprexa or Risperdal
in an eight-year period. The drugs had 384 reported cases, 289 cases
and 132 cases, respectively. On Clozaril, 25 patients died; on Zyprexa,
28; and on Risperdal, 5. The patients who developed diabetes tended
to be young and male. The data were gathered from reports filed with
the F.D.A. and from medical journals.
The researchers cautioned that reporting of adverse drug reactions
to the F.D.A. is voluntary on the part of doctors, making it hard to
know whether the higher numbers for some drugs truly reflect differences
in relative risk. The agency says the reports it receives represent
perhaps 10 percent of the actual number of adverse reactions.
Another study found higher rates of diabetes for patients on Clozaril,
Zyprexa and Seroquel but not Risperdal.
In their study of Zyprexa, published last year in the journal Pharmacotherapy,
Dr. Koller, an endocrinologist then working at the F.D.A., and Dr. Doraiswamy
concluded that the number of cases, the timing of the illnesses and
the relatively young ages of the patients who fell ill "suggest
a causal relationship" between the drug and the development or
worsening of diabetes. Also suggestive, they wrote, was that many patients
improved when the drug was stopped.
Marni Lemons, a spokeswoman for Eli Lilly, which has been served with
five lawsuits involving patients who developed diabetes while on Zyprexa,
said the company did not believe its product was causing diabetes. "This
is not an issue for a specific drug, but for this patient population,"
Ms. Moran, the Novartis spokeswoman, said, "At this time, there
is no evidence suggesting" that diabetes is more common or more
serious in patients on Clozaril than "outside the context of Clozaril
The issue is far from settled, and more than 20 papers on the topic
will are being presented at the psychiatric meetings.
The F.D.A. is also looking closely at the diabetes issues. A spokeswoman
said the agency is waiting for the findings of a large analysis by the
Veterans Administration, to be completed this year, before deciding
whether to require warning labels on some or all of the atypicals. Some
drugs already carry such labels in Japan or Europe, including Zyprexa
However, psychiatrists say patients taking antipsychotic drugs should
be monitored on a regular basis for glucose abnormalities.
Eventually, Dr. Geddes said, the two classes of antipsychotic medication
may come down to a tradeoff of side effects: The risk of tardive dyskinesia
posed by the older drugs versus the risk of diabetes.
"It's not up to me to say, is it?" Dr. Geddes asked. "It's
up to the patient to say."
The FutureCost, Consequences And Patients in Need
Of the billions of dollars spent each year on antipsychotic drugs,
a large part comes from government insurance programs.
Dr. Joseph Parks, the medical director of Missouri's Department of
Mental Health, said that his state spent $104 million, or 11.6 percent
of the total Medicaid payout, on three atypical antipsychotics, Zyprexa,
Risperdal and Seroquel, between April 2002 and March 2003. The three
drugs topped the list in dollar volume of all drugs covered by the state
Medicaid program, including cancer, H.I.V. and heart medications.
"They are good medications," said Dr. Parks, who is also
the president of the National Association of State Mental Health Directors'
medical directors' council, "and they seriously help a lot of people.
I would not want to give up any of them."
But for the price of treating one person with Zyprexa at $303 for a
month's prescription, he said, or two on Risperdal, at $159 per month,
the state could treat 8 or 10 people with Haldol at $35 per month.
Ohio, a larger state, spent $174 million on antipsychotic medications
in 2002, close to $145 million of that on the atypical drugs, said Dennis
Evans, a spokesman for the state's Medicaid program.
Yesterday, researchers at the psychiatric meetings presented a study
of the cost effectiveness of Zyprexa in treating patients at 17 Veterans
Affairs medical centers. The study, led by Dr. Robert Rosenheck, a professor
of psychiatry and public health at Yale and the director of the Department
of Veterans Affairs Northeast Program Evaluation Center, found that
Zyprexa cost the V.A. $3,000 to $9,000 more per patient, with no benefit
to symptoms, Parkinson's-like side effects or overall quality of life.
Zyprexa was less likely to produce the physical restlessness called
akisthesia, the study found, and was associated with slightly better
memory and motor skills. The study was financed by Eli Lilly.
Advocacy groups like the National Mental Health Association worry that
the price difference in the drug classes might cause some states, pressed
by shrinking budgets, to include only some atypicals in their formularies
or even to eliminate them altogether.
Because different drugs work for different people, said Jennifer Bright,
the association's senior policy director for health care reform, forcing
people to choose from two or three medications increases the chances
that none will work, and increases the risk of hospitalization or other,
higher cost care.
"We believe there ought to be open access to all medications,"
Whatever the final verdict on the atypicals, many experts believe what
is really needed is new and better drugs.
Meanwhile, few psychiatrists - and perhaps even fewer patients - would
want to lose any of the newer generation of antipsychotics now on the
market. But how they are used and how much value they add, experts say,
is ultimately a question for society.
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Risperdal (Risperidone) Quick Dissolve Tablets Launched In US
TITUSVILLE, NJ -- May 6, 2003 -- A new, fast-dissolving form of
the schizophrenia medication Risperdal® (risperidone) is launching
this week. Risperdal M-TAB(tm) dissolves in seconds when placed on the
tongue. Risperdal, marketed by Janssen Pharmaceutica Products, L.P.,
is the most widely prescribed antipsychotic medication in the United
"Many individuals can't, won't or just would prefer not to swallow
pills. Having an option like Risperdal M-Tab will be useful in helping
to ensure patients are able to take their medication regularly,"
said Dilip Jeste, MD, professor of psychiatry and neurosciences and
chief of the Division of Geriatric Psychiatry at the University of California,
San Diego (UCSD).
Atypical antipsychotic medications are the most commonly prescribed
treatments for schizophrenia -- a disease that affects 2 million Americans
and includes symptoms such as agitation, depression, anxiety, delusions,
social withdrawal and a diminished capacity for organized thought.
Risperdal M-Tab tablets are produced using freeze-drying technology,
creating highly porous tablets that rapidly disintegrate upon contact
with saliva. The coral-colored, peppermint-flavored tablets will be
available in 0.5 mg, 1 mg and 2 mg doses and are bioequivalent to comparable
dosages of the original-formulation tablets.
In clinical trials, Risperdal was generally well tolerated. However,
as with all other psychotropic medications, Risperdal is associated
with side effects. In two controlled trials involving individuals with
schizophrenia or schizoaffective disorder, adverse events with an incidence
of 5 percent or greater in at least one of the Risperdal groups and
that occurred at a rate that was at least twice that of placebo were
anxiety, drowsiness, extrapyramidal symptoms (uncontrolled tremors and
muscle stiffness), dizziness, constipation, nausea, dyspepsia (upset
stomach), rhinitis (runny nose), rash and tachycardia (rapid heart beat).
For more information, refer to the full prescribing information for
Risperdal or visit http://www.risperdal.com.